Blood pressure (hereinafter referred to as “BP”) is defined by a number of haemodynamic parameters taken either in isolation or in combination. Systolic blood pressure (hereinafter referred to as “SBP”) is the peak pressure exerted on the walls of the arteries during the contraction phase of the ventricles of the heart. Diastolic blood pressure (hereinafter referred to as “DBP”) is the minimum pressure exerted on the vessel walls when the heart muscle relaxes between beats and is filling with blood. The mean arterial blood pressure is the product of cardiac out put and peripheral vascular resistance.
Pre-hypertension has been defined as a SBP in the range of from 120 mmHg to 139 mmHG and/or a DBP in the range of from 80 mmHg to 89 mmHg. Pre-hypertension is considered to be a precursor of hypertension and a predictor of excessive cardiovascular risk (Julius, S., et al., N. Engl. J. Med., 354:1685-1697 (2006)).
Hypertension, or elevated BP, has been defined as a SBP of at least 140 mmHg and/or a DBP of at least 90 mmHg. By this definition, the prevalence of hypertension in developed countries is about 20% of the adult population, rising to about 60-70% of those aged 60 or more, although a significant fraction of these hypertensive subjects have normal BP when this is measured in a non-clinical setting. Hypertension in individuals with diabetes or renal impairment has been defined as a SBP of at least 130 mmHg and/or a DBP of at least 80 mmHg. Some 60% of this older hypertensive population have isolated systolic hypertension, i.e. they have an elevated SBP and a normal DBP. Hypertension is associated with an increased risk of cardiovascular death, stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment (Fagard, R. H., Am. J. Geriatric Cardiology, 11(1), 23-28 (2002); Brown, M J and Haycock, S; Drugs, 59(Suppl 2), 1-12 (2000)).
The pathophysiology of hypertension is the subject of continuing debate. While it is generally agreed that hypertension is the result of an imbalance between cardiac output and peripheral vascular resistance, and that most hypertensive subjects have normal cardiac output and increased peripheral resistance there is uncertainty which parameter changes first (Beevers, G et al., BMJ, 322, 912-916 (2001)).
Chlorthalidone, also known as, benzenesulfonamide, 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1yl) or 2-chloro-5-(1-hydroxy-3-oxo-1,2-dihydroisoindol-1-yl)-benzenesulfonamide, is a long-acting diuretic. Chlorthalidone is an effective treatment to lower elevated arterial blood pressure (arterial hypertension). U.S. Pat. No. 3,055,904 discloses daily doses of chlorthalidone in the amount of 50 mg to 200 mg orally one to three times a day or 100 mg every second day for use as a diuretic. U.S. Pat. No. 5,948,799 discloses a typical range of chlorthalidone of 6.25-200 mg daily and a preferred range of 12.5 to 100 mg daily for use in the treatment of non-ischemic congestive heart failure in combination with amlodipine and/or digoxin. U.S. Patent Application No. 2007/0004792 discloses a method for the treatment of systemic arterial hypertension, which is based on the oral administration to a patient suffering from systemic arterial hypertension either chlorthalidone alone in the amount of 2.5-10 mg daily, or in combination with another anti-hypertensive agent, such as angiotensin converting enzyme inhibitor, angiotensin receptor blocker, calcium antagonist (calcium channel blocker), aldosterone antagonist, beta blocker, alpha blocker.
Thiazide-type diuretics, which includes chlorthalidone, have been effectively used in long-term monotherapy to lower blood pressure, enhance the efficacy of other antihypertensive agents, and reduce cardiovascular events. (Ernst, M., et al., N. Engl. J. Med., 361:2153-2164 (2009)).
Although used to treat hypertension, chlorthalidone is known to cause a number of side effects. These side effects include, but are not limited to, gastrointestinal system reactions (such as, anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (such as, intrahepatic cholestatic jaundice), pancreatitis), central nervous system reactions (such as, dizziness, vertigo, paresthesias, headache, xanthopsia), hematologic reactions (such as, leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia), dermatologic-hypersensitivity reactions (such as, purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell's syndrome (toxic epidermal necrolysis), cardiovascular reaction (such as, orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates or narcotics and other adverse reactions (such as, hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, impotence, azotemia, hypokalemia, hypercalcemia, and hyponatremia).
Chlorthalidone has been combined with antihypertensive agents for use in the treatment of hypertension. For example, CLOPRES® is a combination of clonidine hydrochloride (a centrally acting antihypertensive agent is a class of drugs that is different than angiotensin II receptor blockers (ARBs)) and chlorthalidone for oral administration in three dosage strengths, 0.1 mg/15 mg, 0.2 mg/15 mg and 0.3 mg/15 mg of clonidine hydrochloride/chlorthalidone, respectively.
Angiotensin II receptor blockers (ARB) specifically antagonize or block the action of angiotensin II type 1 receptors. This results in an inhibition of the physiological action of angiotensin II. Angiotensin II is generated as a part of the renin-angiotensin system, and has a strong hypertensive action. A number of ARBs are known in the art. Examples include, losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan, tasosartan, zolarsartan, olmesartan, certain benzimidazole derivatives having ARB activity (as defined herein) and certain heterocyclic compounds having ARB activity (as defined herein). Combinations of ARBs and diuretics, such as hydrochlorothiazide (HCTZ), are also known.
For example, WO 2005/014043 discloses bilayer tablets comprising 10-800 mg of an ARB and 6.25-50 mg of chlorthalidone for use in treating hypertension. WO 2005/014043 also discloses bilayer tablets comprising 40, 80 mg of sodium salt of telmisartan and 12.5, 25 mg of chlorthalidone for use in treating hypertension. Furthermore, WO 2005/014043 discloses an amount of ARB in a single dosage form in the range of 10-800 mg. Depending on the ARB used, the preferred ranges disclosed are 150-300 mg (e.g. irbesartan), 60-90 mg (e.g. valsartan or telmisartan), 30-60 mg (e.g. telmisartan or losartan) or 15-30 mg (e.g. candesartan). The particularly preferred ranges are 80-85 mg, 40-45 mg or 20-25 mg. The amount of chlorthalidone in a single dosage form is in the range of 10-15 mg or 20-30 mg, preferably 12-13 mg or 24-26 mg.
PCT/JP2009/063833 discloses a solid preparation comprising 0.1-60 weight percentage of a benzimidazole derivative having a strong angiotensin II receptor antagonistic activity and 0.1-60 weight percentage of chlorthalidone for use in treating hypertension. Also disclosed are preparations comprising 21.34, 42.68, 43.465 and 85.36 mg of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate potassium salt and 6.25, 12.5, 25 mg of chlorthalidone for use in treating hypertension. Additionally, PCT/JP2009/063833 discloses the dose of benzimidazole derivative administered to patients is determined based on age, body weight, general health condition, sex, diet, administration time, clearance rate, combination of drugs and the like, as well as the severity of the disease for which the patient is undergoing treatments. Specifically, daily doses in the amount of about 0.05-500 mg, preferably 0.1-100 mg are disclosed. The dose of a diuretic to patients is determined based on age, body weight, general health condition, sex, diet, administration time, clearance rate, combination of drugs and the like, as well as the severity of the disease for which the patient is undergoing treatments. Specifically, the daily dose of diuretic is, for example, about 12.5-100 mg, preferably 15-50 mg, of chlorthalidone (converted into free form). In the case of hydrochlorothiazide (converted into free form), the daily dose is about 12.5-100 mg, preferably 15-50 mg.
However, there is a need in the art for new combinations and dosing regimens for such ARBs and diuretics that exhibit superior efficacy in treating hypertension and that may also exhibit reduced side effects.